Abstract Many patients suffering from HIV will develop distal symmetrical neuropathy that is frequently accompanied by pain. In some patients, HIV antiretroviral treatments can elicit and exacerbate neuropathic pain. The mechanisms underlying HIV neuropathic pain (HIVNP) are not well understood. HIVNP is relatively resistant to treatments commonly used for other types of neuropathic pain (e.g., reuptake blockers, gabapentinoids). Clinically significant effects of smoked cannabis have been reported in HIVNP, suggesting that cannabinoid activity may provide significant analgesic benefit in these patients. First, we shall develop novel CB2 agonists with no or very low functional efficacy for CB1, with improved pharmacological profiles based on the AM1710 chemotype. These novel compounds will be potent CV2 agonists and neutral CB1 antagonists. The second approach will involve the design and synthesis of novel CB1/CB2 agonists that are peripherally acting. We shall seek to obtain novel compounds in which the CB2/CB1 contributions to their respective effects on HIVNP is optimized. We have shown that AM1710, a selective CB2 agonist developed in our laboratory, elicits analgesic actions in a model of HIVNP. We propose that CB2 agonists could prove to be an effective strategy for non-addictive treatment of HIVNP and possibly for other chronic pain conditions. We propose two approaches. Both approaches will develop novel ligands that encompass design controlled cannabinoid deactivation, a concept recently developed in our laboratory for cannabinergic compounds. This involves the introduction within each ligand of a serum esterase susceptible moiety, which when subjected to the enzyme?s hydrolytic action, transforms the molecule into inactive metabolites. The duration of action in vivo of the new compounds is controlled by the chemical nature and environment of the sessile group, as well as by the degree to which the novel compound is subject to a depot effect, a property largely controlled by the compound?s hydrophobic character. The project will involve 1) the design and synthesis of the novel ligands and 2) in vitro characterization evaluation for their CB2 and CB1 affinities and functional potencies, as well as their biochemical stabilities, or bioavailabilities, and abilities (or lack of) to cross the blood brain barrier. The successful compounds will be screened (Biochemical Core) for their effects in models of inflammatory pain. 3) A select number of compounds will be tested for their efficacy in a HIV neuropathic pain model for their side effects, tolerance, and potential abuse liability.